Anorexigenic compositions comprising 6-alkyl-1,2,3,4,5,6-hexahydroazepino 4,5-indoles as active ingredient and process of treatment

ABSTRACT

Compositions comprising 6-alkyl-1,2,3,4,5,6hexahydroazepino(4,5-b)indole of the formula:   WHEREIN R and R&#39;&#39; are selected from the group consisting of hydrogen, alkoxy and alkyl containing from one to three carbon atoms, inclusive, and halogen; wherein R1 is alkyl defined as above; including pharmacologically acceptable acid addition salts of those compounds, in combination with conventional pharmaceutical carriers. The compositions are used to suppress hunger in mammals.

United States Patent Hester, Jr.

[ 1 July 11, 1972 [54] ANOREXIGENIC COMPOSITIONS COMPRISING6-ALKYL-1,2,3,4,5,6- HEXAl-IYDROAZEPINO 4,5-INDOLES AS ACTIVE INGREDIENTAND PROCESS OF TREATMENT [63] Continuation-impart of Ser. No. 868,927,Oct. 23, 1969, which is a continuation of Ser. No. 548,880, May 10,I966, abandoned.

52 us. CI ..424/274 [5 l Int. Cl. A6lk 27/00 [58] Field of Search..424/274 [56] References Cited UNITED STATES PATENTS 3,525,750 8/1970Renner ..260/326.5

Primary Examiner-Jerome D. Goldberg Attomey-John Kekich and John J.Killinger ABSTRACT Compositions comprising 6-alkyll,2,3,4,5,6-hexahydroazepino[4,5blindole of the formula:

R (Formula VI) wherein R and R are selected from the group consisting ofhydrogen, alkoxy and alkyl containing from one to three carbon atoms,inclusive, and halogen; wherein R is alkyl defined as above; includingpharmacologically acceptable acid addition salts of those compounds, incombination with conventional pharmaceutical carriers. The compositionsare used to suppress hunger in mammals.

8 Claims, No Drawings ANOREXIGENIC COMPOSITIONS COMPRISING 6- ALKYL- 1,2,3,4,5,6-IIEXAHYDROAZEPINO 4,5-INDOLES AS ACTIVE INGREDIENT ANDPROCESS OF TREATMENT CROSS-REFERENCES TO RELATED APPLICATIONS Thisapplication is a continuation-in-part of application, Ser. No.868,927,filed Oct. 23, 1969, which in turn is a continuation-in-part ofapplication, Ser. No. 548,880, filed May I0, 1966, now abandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to pharmaceuticalcompositions prepared in unit dosage form comprising from about 5 toabout 500 mg. of a compound of the formula:

(Formula VI) DETAILED DESCRIPTION Compounds of the Formula VI andpharmacologically acceptable acid addition salts thereof can be preparedby methods disclosed in French Special Medicinal Pat. No. 1,524,495filedMay 9, I967 and issued Apr. 1, 1968.

A compound of the Formula VI or pharmacologically acceptable acidaddition salts thereof are presented for oral administration in solidand liquid unit dosage forms, such as tablets, coated and uncoated,capsules, powders, granules, syrups, elixirs, and the like, containingsuitable quantities of the compound.

Powders are quite simply prepared by comminuting a compound of theFormula VI or pharmacologically acceptable acid addition salts thereofto a suitable fine size and mixing with a similarly comminuted diluent.The diluent can be an edible carbohydrate material such as starch orlactose. Advantageously, a sweetening agent or sugar is present as wellas a flavoring. Dry granulations for reconstruction with water areprepared utilizing water-soluble diluents. A powder mixture of finelydivided compound of the Formula VI or pharmacologically acceptable acidaddition salts thereof and a water-soluble diluent such as sucrose,glucose, and the like, is wetted with a binder such as acacia mucilageor gelatin solution and forced through a screen to form granules whichare allowed to dry. Advantageously, a thickening or suspending agentsuch as methylcellulose is present as well as a wetting agent andflavoring.

Capsules are produced by preparing a powder mixture as hereinbeforedescribed and filling into formed gelatin sheaths. Advantageously, as anadjuvant to the filling operation, a lubricant such as talc, magnesiumstearate and calcium stearate is added to the powder mixture before thefilling operation.

Tablets are made by preparing a powder mixture, wet granulating or drygranulating by slugging, adding a lubricant and pressing into tablets.The powder mixture is prepared by mixing a compound of the Formula VIand pharmacologically acceptable acid addition salts thereof suitablycomminuted, with a diluent or base such as starch, lactose, kaolin,dicalcium phosphate and the like. The powder mixture can be granulatedby wetting with a binder such as corn syrup, gelatin solution,methylcellulose solution or acacia mucilage and forcing through ascreen. An alternative granulating procedure is by slugging the powdermixture, i.e., run the powder mixture through a tablet machine and theresulting large tablets broken into pieces (slugs). The slugs can belubricated to prevent sticking to the tablet-forming dies by means ofthe addition of stearic acid, a stearate salt, talc, or mineral oil. Thelubricated mixture is then compressed into tablets of the requiredweight.

Advantageously, the tablet can be provided with a protective coatingconsisting of a sealing coat of shellac, a coating of sugar andmethylcellulose and a polish coating of carnauba wax.

Oral fluids are prepared in unit dosage forms such as syrups and elixirswherein each teaspoonful of composition contains a predetermined amountof a compound of the Formula VI and pharmacologically acceptable acidaddition salts thereof for administration.

A syrup is prepared using a water soluble salt of a compound of theFormula VI in a suitable flavored aqueous sucrose solution. Similarly anelixir is prepared utilizing a hydroalcoholic vehicle. Elixirs areadvantageous vehicles for use when another therapeutic agent which isnot sufficiently water soluble is to be included in the composition.

For parenteral administration aqueous fluid unit dosage forms can beprepared. In preparing the parenteral form, a measured amount of a watersoluble salt of a compound of the Formula VI and a pharmacologicallyacceptable acid is placed in a via], the vial and its contentssterilized and sealed. An accompanying vial of sterile water is providedas a vehicle to form a solution prior to administration. Advantageously,the sterile water can have dissolved therein a local anesthetic andbuffering agents. I

Alternatively, a parenteral suspension can be prepared by suspending aninsoluble form of a compound of the Formula VI in a sterile aqueousvehicle or in a parenterally acceptable vegetable oil with or withoutadditional adjuvants.

In addition to oral and parenteral administration, the rectal route canbe utilized. A compound of the Formula VI and pharmacologicallyacceptable acid addition salts thereof can be administered by means of asuppository. A vehicle which has a melting point at about bodytemperature or one that is readily soluble can be utilized. For example,cocoa butter and various solid polyethylene glycols can serve as thevehicle.

For the treatment of domestic birds and animals by oral administration,a compound of the Formula VI and pharmacologically acceptable acidaddition salts thereof is conveniently prepared in the form of a foodpremix. The food premix can comprise the active material in admixturewith an edible diluent such as starch, oatmeal, flour, calciumcarbonate, talc, dried fish meal and the like non-toxic, orallyacceptable edible diluents. The prepared premix is then convenientlyadded to the regular feed, thereby providing medication to the animal orbird in the course of feeding.

The compositions of the present invention have anorexigenic activity.The compositions are useful in the treatment of obesity.

The amount of a compound of the Formula VI and pharmacologicallyacceptable acid addition salts thereof to be administered varies withthe weight, age, condition, route of administration and species ofanimal. In general a dose of from about 0.3 to about 250 mg./kg./day andpreferably from about 1 to about 75 mg./kg./day is administered. Thehuman daily dose can be from about 5 to about 1000 mg. in single ordivided doses and preferably divided doses of 10 to 250 mg. beforemeals.

Conveniently the compositions are prepared in dosage unit v form of fromabout 10 to about 250 mg. per dosage unit.

In addition to the administration of a compound of the Formula VI andpharmacologically acceptable acid addition salts thereof as theprincipal active ingredient of compositions described herein, the saidcompound can be included with other types of active anorexigeniccompounds, sedatives and tranquilizers to obtain advantageouscombinations of properties with the following ingredients inapproximately the indicated amounts: d-amphetamine sulfate (2-l0 mg);methamphetamine (2-l0 mg.); benzphetamine (10-50 mg);

phenmetrazine (5-25 mg.); fenfluramine (5-50 mg.); diethylpropionhydrochloride (2-25 mg.); chlorophentermine hydrochloride (-100 mg.);phenobarbital (5-50 mg.); amobarbital (5-60 mg.); aprobarbital (10-40mg.); butabarbital (8-60 mg.); pentobarbital (-40 mg.); chlorpromazine(10-50 mg.); fluphenazine (2-l0 mg.); meprobamate (100-400 mg.); andphenaglycodol (100-600 mg.).

Formula VI wherein R and R are selected from the group consisting ofhydrogen, alkoxy and alkyl containing from one to three carbon atoms,inclusive, and halogen, with the proviso that at least one of the twoother positions (to the hydrazino group) in compound I is hydrogen;wherein R" is selected from the group consisting of alkyl containingfrom 1 to 3 carbon atoms, inclusive.

The preparation of the active compounds consists of: heating aphenylhydrazine of Formula I with l-benzoylhexahydro- 4H-azepin-4-one toobtain the corresponding phenylhydrazone ofl-benzoylhexahydro-4H-azepin-4-one (11); heat- 11 with formic acid toobtain the corresponding3-benzoyll,2,3,4,5,6-hexahydroazepino[4,5-b]indole (lll); reducing lllwith a metal hydride, e.g., lithium aluminum hydride, to obtain thecorresponding 3-benzyll ,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1V);hydrogenolyzing 1V in the presence of a palladium catalyst to give thecorresponding l,2,3,4,5,6-hexahydroazepino[4,5-b]indole (V); alkylatingcompound V with an alkyl halide in which the alkyl is methyl, ethyl,propyl or isopropyl and the halogen is bromine or iodine in the presenceof sodium hydride to give the corresponding 6- alkyl1,2,3,4,5,6-hexahydroazepino[4,5-b1indole (VI) often isolated as thehydrochloride, hydrobromide or hydroiodide.

ln carrying out the process, the selected phenylhydrazine of Formula Iis refluxed with 1-benzoyl-hexahydro-4H-azepin-4- one in a solvent suchas ethanol, benzene, toluene or the like. In the preferred method, anacid catalyst such as acetic acid in a quantity of about 0.25 to 1.5percent, calculated on the amount of solvent, is added to obtain higheryields. The total time of the reaction may vary between half an hour and4 hours at the reflux temperature of the solvent. At the termination ofthe reaction, the product is isolated by conventional means such as bycrystallization, filtration, extraction and the like.

The thus-obtained 1-benzoylhexahydro-4l-l-azepin-4-one phenylhydrazone(II) is thereupon heated with formic acid of a concentration of 88 to 99percent for a period usually between 10 minutes and 2 hours in order toprovide crude 3- benzoyl-l,2,3,4,5,6-hexahydroazepino[4,5-blindole (lll)which is isolated and purified by conventional procedures, such aspouring the reaction mixture into ice water, collecting the resultingproduct by filtration and recrystallizing, chromatographing, orextracting the product to obtain the pure 3- benzoyl-l,2,3,4,5,6-hexahydroazepino-[4,5-b]indole (lll The thus-obtained3-benzoyl-l ,2,3,4,5,6-hexahydroazepino[4,5-b]indole is reduced with ametal hydride, preferably lithium aluminum hydride, in tetrahydrofuransolution. The reaction is, at first, generally carried out undernitrogen during a period of about one-half hour to 8 hours at about roomtemperature, that is, between 20-30 C. Higher or lower temperatures inthe initial phase can be used. Thereafter, the temperature is increasedto the reflux temperature of the mixture, and the mixture is heated fora period between 6 to 24 hours. The products are obtained by decomposingthe reaction mixture, after cooling, with water and a base such assodium hydroxide or potassium hydroxide and filtering the solution.Concentration of the filtrate gives the desired3-benzyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1V).

Removal of the benzyl group of the 3-benzyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole is achieved by hydrogenolysis in thepresence of a Nobel metal catalyst, e.g., a palladium or platinumcatalyst (5 to 10 percent platinum or palladium on a carbon carrier).The hydrogenolysis may be carried out at a pressure between 10 to 75pounds of hydrogen and is generally completed within between 1 to 8hours at room temperature. At the termination of the reaction, thecatalyst is removed by filtration, the filtrate is concentrated and thecrude product purified in conventional manner, such as byrecrystallization, formation of a salt and treating the salt with abase, or the like.

The thus-obtained l,2,3,4,5,6-hexahydroazepino[4,5-b]-indole (V) isalkylated in the 6-position, in conventional manner, with an alkylbromide or alkyl iodide such as methyl, ethyl, propyl, isopropyl bromideor iodide.

Preparation 1 l-Benzoylhexahydro-4H-azepin-4-one A.l-benzoylhexamethyleneimine [l-benzoylhexahydro-4 H-azepine] Benzoylchloride (60 ml.) in 200 ml. of Skellysolve B hexanes was added to astirred, cooled (ice-bath) solution of 200 ml. of hexamethyleneimine in800 ml. of Skellysolve B hexanes. The mixture was then washed severaltimes with 1N hydrochloric acid and with water, and filtered throughanhydrous sodium sulfate. Evaporation of the Skellysolve B hexanes anddistillation of the oily residue gave 40.5 g. oflbenozylhexamethyleneimine, b.p. l50-l60 C./l torr. Analysis:

Calcd. for C H NO:

Found:

B. Fermentation of l-benzoylhexamethyleneimine A medium was prepared of200 g. of cornsteep liquor (60 percent solids), g. of commercialdextrose, and 101. of tap water. The pH was adjusted to between 4.8 and5 and 10 ml. of lard oil was added as a foam preventive. This medium wassterilized and inoculated with a 72-hour vegetative growth ofSporotriclium .rulfurescens, ATCC 7159, and after incubation for 24hours at a temperature of about 28 C. using a rate of aeration of 0.5 l.per minute and agitation of 300 r.p.m., the substrate, 2 g. of acetone(about 20 ml.) was then added to the fermentation. After an additional72-hour period of incubation at the same temperature and aeration, thebeer and mycelium were separated by filtration. The mycelium was washedwith water and the wash water was added to the beer filtrate. Thethus-obtained beer filtrate was extracted four times with a volume ofmethylene chloride equal to one-fourth the volume of the filtrate. Thecombined extracts were washed with one-fourth volume of distilled waterand the solvent was removed by distillation to give a residue.

The residue thus obtained was chromatographed on Florisil and elutedwith Skellysolve B hexanes containing increasing portions of acetone.The 25 percent acetone-75 percent Skellysolve B hexanes eluate gaveabout 250 mg. of l-benzoylhexahydro-4H-azepin-4-one and the acetoneeluate gave 1- benzoyl-4-hydroxyhexahydro-4H-azepine determined by thinlayer chromatography.

C. Oxidation of l-benzoyl-4-hydroxyhexahydro-4l-l-azepine Thel-benzoyl-4-hydroxyhexahydro-4H-azepine thus obtained was dissolved inacetone and oxidized at room temperature by the addition of a visibleexcess of Jones reagent (2.67M chromic acid reagent prepared from 26.7g. of chromium trioxide and 23 ml. of sulfuric acid, diluted to 100 ml.with water). The excess oxidant was destroyed by the addition ofisopropyl alcohol and the mixture was evaporated to dryness. Water (20ml.) was added, and the product was extracted with 20 ml. of methylenechloride. The extract was evaporated to dryness and the residuall-benzoylhexahydro- 4l-1-azepin-4-one thus obtained was combined withthe same product obtained directly from the bioconversion. The combinedproduct was chromatographed on a column of Florisil (anhydrous magnesiumsilicate). The column was eluted with Skellysolve B hexanes containingincreasing proportions of acetone and those fractions containing thedesired product, as determined by thin layer chromatography, werecombined and evaporated to give about 770 mg. of l-benzoylhexahydro-4H-azepin-4-one as an oil, b.p. 170-l74 C./0.3 torr.-, that crystallizedslowly.

Analysis:

Calcd. for C I-1 N 2 C, 71.86; H, 6.96; N, 6.45. Found:

C, 71.51; H, 7.25; N, 6.46.

Preparation 2 Phenylhydrazone of l-benzoylhexahydro-4H- uzcpin-4-onc Amixture of 20 g. (0.092 mole) of l-benzoylhexahydro- 4H-azepin-40ne.10.5 g. of phenylhydrazine (0.097 mole), 200 ml. of absolute ethanol and1.5 ml. of acetic acid was refluxed for a period of 1 hour and thencooled in an ice bath. Crystals formed which were collected byfiltration, washed with ethanol and dried to yield 20.8 g. (74 percent)of the phenylhydrazone of 1-benzoylhexahydro-4H-azepin-4-one of meltingpoint 185-190 C.

Preparation 3 p-Methoxyphenylhydrazone ofl-benzoylhexahydro-4H-azepin-4- one A solution of 120.1 g. (0.869 mole)of p-methoxyphenylhydrazine, 172.0 g. (0.792 mole) ofl-benzoylhexahydro-4H- azepin-4-one and 12.9 ml. of glacial acetic acidin 1,725 ml. of absolute ethanol was refluxed in a nitrogen atmospherefor a period of 1 hour. The reaction mixture was then cooled andconcentrated under reduced pressure. The product which had crystallizedfrom the solution was collected by filtration, washed with ethanol anddried to give 108.9 g. of l-benzoylhexahydro-4H-azepin-4-onep-methoxyphenylhydrazone of melting point l55.5l66.5 C. A second cropwas obtained by concentrating the mother liquors, providing anadditional amount of 32.9 g. so that the total yield was 53 percent.Preparation 4 m-Methoxyphenylhydrazone ofl-benzoylhexahydro-4H-azepin-4-one To a 3N aqueous sodium hydroxidesolution (300 ml.) and ether (300 ml.) was added 62.7 g. (0.360 mole) ofm-methoxyphenylhydrazine hydrochloride. This mixture was stirred untilthe material went into solution, the ether layer was separated and theaqueous layer extracted with additional ether. The ether layer andextracts were washed with brine, dried over anhydrous potassiumcarbonate and concentrated under reduced pressure at about 25 C. to givea residue. To a solution of the residue in 500 ml. of ethanol was addeda solution of l-benzoylhexahydro-4H-azepin-4-one (65 g.; 0.3 mole) in300 ml. of ethanol and 5 ml. of acetic acid. The resulting solution wasrefluxed under nitrogen for 1 hour and then concentrated under reducedpressure. The product which crystallized from the partially concentratedreaction mixture was collected by filtration, washed with ethanol anddried to give 45.2 g. (44.7 percent) of m-methoxyphenylhydrazone of1-benzoylhexahydro-4l-l-azepin-4-one of melting point l53-159 C.Preparation 5 oMethoxyphenylhydrazone ofl-benzoylhexahydro-4H-azepin-4-one To a stirred mixture of 3N aqueoussodium hydroxide (300 ml.) and 300 ml. of ether was added 62.7 g. (0.360mole) of omethoxyphenylhydrazine hydrochloride. After solution wasachieved, the aqueous layer was saturated with sodium chloride,separated from the ether layer and and extracted with ether. Thecombined ether layer and extracts were washed with brine, dried overpotassium carbonate and concentrated under reduced pressure at 25 C. togive a residue. The residue was dissolved in 500 ml. of ethanol and wasthus added to a solution of 65 g. (0.300 mole) ofl-benzoylhexahydro-4H-azepin-4-one in 300 ml. of ethanol and 5 ml. ofacetic acid. The mixture was refluxed for 1 hour and concentrated underreduced pressure. The resulting residue was crystallized from ethanol togive a total of 34.3 g. of o-methoxyphenylhydrazone of1-benz0ylhexahydro-4H-azepin-4-one of melting point -154 C. Preparation6 3-Benzoyl-l,2,3,4,5,6-hexahydroazepino[4,5- b]indole A mixture of 5 g.(16.3 moles) of the phenylhydrazone of lbenzoylhexahydro-4H-azepin-4-oneand 35 ml. of 97 percent formic acid was heated on the steam bath in anitrogen atmosphere for 20 minutes. It was then poured into ice watergiving a dark brown solid which was collected by filtration, washed withwater and dried in vacuo to yield 4.5 g. of a crude product. Thismaterial was chromatographed over 300 g. of silica gel with mixtures of15-30 percent acetone, balance cyclohexane. The product thus obtainedwas evaporated and crystallized from methanol-water to give 1.9 g. (40percent) of 3-benzoyll ,2,3,4,5,6-hexahydroazepino[4,5-b]indole ofmelting point l69l 70 C. Analysis:

Calcd. for C H N O:

C, 78.59; H, 6.25; N, 9.65. Found:

C, 78,26; H, 6.22; N, 9.43. Preparation 7 3-Benzoyl-9-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5b]indole To 100 ml. of about 3N hydrogenchloride solution in absolute ethanol was added 3.37 g. (0.010 mole) ofp-methoxyphenylhydrazone of 1-benzoylhexahydro-4H-azepin-4-one. Thismixture was heated on the steam bath for a period of 7 minutes, thenpoured into ice water. The solid was collected by filtration, washedwith water and dissolved in methylene chloride. The methylene chloridesolution was dried over anhydrous magnesium sulfate, concentrated toabout 10 ml. and poured over a column containing 250 g. of neutralalumina. The column was eluted with 80 percent ethyl acetate-20 percentSkellysolve B hexanes and the resulting product crystallized from ethylacetate to yield 0.3 g. (9.37 percent) of 3- benzoyl-9-methoxyl,2,3,4,5,6-hexahydroa2epino[4,5,-b]indole of melting point l29.5-133 C.(dec. Preparation 83-Benzoyl-8-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole and3-benzoyl-l0-methoxyl,2,3,4,5,6-hexahydroazepino-[ 4,5-b]indole Amixture of 43.9 g. (0.130 mole) of the m-methoxyphenylhydrazone ofl-benzoylhexahydro-4H-azepin-4-one and ml. of 88 percent formic acid washeated on the steam bath in a nitrogen atmosphere for a period of 30minutes. It was then cooled and poured into ice water. The resultingmixture was extracted with chloroform, the chloroform extracts werewashed with water, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was chromotographed over2.2 kg. of silica gel with a mixture of 60 percent ethyl acetate-40percent cyclohexane. Twenty-five 1.5 1. fractions were collected. Thefirst band, obtained from fractions 8-1 1, was crystallized frommethylene chloride-ethyl acetate to yield 2.66 g. of3-benzoyl-l0-methoxy-l,2,3,4,5,6-

hexahydroazepino[4,5]-indo1e of melting point 263.5-267 C. A second cropof this material was obtained weighing 0.185 g. (total yield 6.82percent). The product when recrystallized from methylenechloride-methanol gave pure 3-benzoy1-10-methoxy-l,2,3,4,5,6-hexahydroazepinol4,5-blindole of melting point264.5-266.5 C. Analysis:

Calcd. for C H N O C, 74.97; H, 6.29; N, 8.74. Found:

C, 74.49; H, 6.63; N, 9.01.

The second isomer, obtained from fractions 14-17 was crystallized frommethylene chloride-ethyl acetate to give 5.86 g. of3-benzoyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole of meltingpoint 201.5-203 C. A second fraction of 3.98 g. of the same material wasalso obtained. Recrystallization of the product from methylenechloride-methanol gave pure 3-benzoyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5,-b]indole of melting point 2O2 203.5 C.

Analysis:

Calcd. for C H N O C, 74.97; H, 6.29; N, 8.74.

Found:

C, 74.77; H, 6.50; N, 8.62. Preparation 9 3-Benzoyl-7-methoxyl,2,3,4,5,6-hexahydroazepino[4,5-b]indole A mixture of 29.9 g. (0.0888mole) of the o-methoxyphenylhydrazone ofl-benzoylhexahydro-4H-azepin-4-one and 88 percent formic acid (120 ml.)was heated on the steam bath in a nitrogen atmosphere for a period of 30minutes and poured thereupon into 2.5 l. of ice water. This mixture wasextracted with chloroform, the chloroform extracts were washed withwater, dried over anhydrous potassium carbonate and concentrated underreduced pressure to give a residue. This residue was chromatographedover silica gel (1.5kg.) and eluted with 60 percent ethyl acetate-40percent cyclohexane. The product thus obtained was crystallized frommethylene chloride-ethyl acetate to give 1.15 g. of3-benzoyl-7-methoxy-l,2,3,4,5,6- hexahydroazepino[4,5]indole of meltingpoint 203204.5 C. A second crop of 0.754 g. was obtained of the samematerial providing a total yield of6.69 percent.

Analysis: -hexahydroazepino-[ Calcd. for C H N O C, 74.97; H, 6.29; N,8.74. Found:

C, 75.00; H, 6.45; N, 8.92.

Preparation 10 3-Benzy1-1,2,3,4,5,6-hexahydroazepino-]4,5- b]indole-hexahydroazepino-{ To a stirred mixture of 6 g. of lithium aluminumhydride in 400 ml. of dry tetrahydrofuran was added a solution of 6 g.(20.6 mmoles) of 3-benzoyl-l ,2,3,4,5,6-hexhydroazepino[ 4,5-b]indole in150 ml. of tetrahydrofuran. The addition was carried out in a nitrogenatmosphere during 1 hour. The resulting mixture was stirred at roomtemperature (about 25 C.) for about 4 hours and then refluxed for 18hours. The mixture was then cooled in an ice bath and treated first with6 ml. of water, then with 6 ml. of percent sodium hydroxide solution andthen with 18 ml. of water. This mixture was stirred for 2 hours and thenfiltered. The filtrate was concentrated under reduced pressure to give aresidue and the residue was crystallized from ethyl acetate-SkellysolveB hexanes to give 3.37 g. (59 percent) of3-benzyl-l,2,3,4,5,6-hexahydroazepine[4,5- blindole of melting pointl16-1l7 C.

Analysis:

Calcd. for C H N C, 82.57; H, 7.30; N, 10.14.

Found:

C, 82.34; H, 7.52; N, 10.04. Preparation 1 l3-Benzyl-9-methoxy-1,2,3,4,5,6-hexmole) of3-benzyol-9-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-blindole and themixture was refluxed in a nitrogen atmosphere for a period of 18 hours.Thereafter, the mixture was cooled in an ice bath and treatedsuccessively with 1 ml. of water, 1 ml. of 15 percent aqueous sodiumhydroxide solution and 3 ml. of water. The resulting mixture wasfiltered and the filtrate concentrated in vacuo to give a solid whichwas recrystallized from ethyl acetate to give 0.773 g. (81 percent) ofproduct which again was recrystallized from ethyl acetate-Skellysolve Bhexanes to give pure 3-benzyl-9-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indo1e of melting point127.5l 29.5 C.

Analysis:

Calcd. for C H N O:

C, 78.40; H, 7.24; N, 9.14. Found:

C, 78,45; H, 7.35; N, 9.42. Preparation 123-Benzyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole To astirred, ice cold suspension of9 g. oflithium aluminum hydride in 900ml. of tetrahydrofuran was added 8.93 g. (0.0279 mole) of3-benzoyl-8-methoxy-l,2,3.4,5,6-hexahydroazepino[4,5-b1indole. Themixture was refluxed in a nitrogen atmosphere for a period of 18 hours,cooled in an ice bath and treated successively with 9 ml. of water, 9ml. of 15 percent aqueous sodium hydroxide and 27 ml. of water. Themixture was then filtered, the filtrate evaporated, the residuecrystallized from ethyl acetate to give 6.62 g. (77.4 percent) ofproduct which upon recrystallization from ethyl acetate gave3-benzyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-] indole of meltingpoint 146.5-147 C.

Analysis:

Calcd. for C ,,H N O:

C, 78.40; H, 7.24; N, 9.14. Found:

C, 78.25; H, 7.44; N, 9.33. Preparation 13 3-Benzy1-l0-methoxy-1,2,3,4,5,6-hexahydroazepino[ 4,5-b]indole To an ice cold, stirredsuspension of lithium aluminum hydride (3 g.) in 300 ml. oftetrahydrofuran was added 2.35 g. (7.26 mmoles) of 3benzoyl-l0-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole. This mixture was refluxed for18 hours in a nitrogen atmosphere then cooled in an ice bath and treatedsuccessively with 3 ml. of water, 3 ml. of 15 percent aqueous sodiumhydroxide and 9 ml. of water. The mixture was thereupon filtered, thecollected solids washed with tetrahydrofuran and the washings andfiltrate combined and concentrated to give a solid crude product. Thisproduct was crystallized from ethyl acetate-Skellysolve B hexanes togive 1.85 g. (83.3 percent) of 3-benzyl-l0-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5l-indole, which after recrystallization from thesame solvent mixture had a melting point of l63.51 64.5 C.

Analysis: Calcd. for C H N O: C, 78.40; h, 7.24; N, 9.14. Found:

C, 78.80; H, 7.42; N, 9.03. Preparation 14 3-Benzyl-7-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride To a stirred,ice-cold suspension of 2 g. oflithium aluminum hydride in 200 ml. oftetrahydrofuran was added 1.85 g. (5.77 mmoles) of 3-benzoyl-7-methoxy-1 ,2,3,4,5 ,6-hexahydroazepino[4,5-b]indole. The resulting mixture wasrefluxed for 18 hours in a nitrogen atmosphere and then decomposed bythe successive addition of 2 ml. of water, 15 percent aqueous sodiumhydroxide (2 ml.) and 6 ml. of water. The resulting mixture was filteredand the filtrate concentrated under reduced pressure to give a residue.A solution of this residue in ethyl acetate was acidified withmethanolic hydrogen chloride, and the resulting crystallinehydrochloride was collected by filtration and dried to yield 1.81 g.(91.5 percent) of benzyl-7-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride of melting point 251-'252.5 C. Therecrystallized material from methanol-ethyl acetate melted at 247248 C.(dec.).

Analysis:

Calcd. for C H ClN O:

C, 70.06; H, 6.76; N, 8.17;C1, 10.34.

Found:

C, 70.15; H, 6.94; N, 8.12; Cl, 10.32.

Preparation 15 l,2,3,4,5,6-Hexahydroazepino[4,5-b]indole andcyclohexanesulfamate thereof A solution of3-benzyl-l,2,3,4,5,6-hexahydroazepino-[4,5- b]indole (l g.; 3.61 mmoles)in 150 ml. ofethanol was treated with 100 mg. of percentpalladium-on-carbon catalyst and hydrogenolyzed in a Parr apparatus atan initial pressure of 50 pounds p.s.i. of hydrogen. After 1.5 hours thereaction was completed and the catalyst removed by filtration. Thefiltrate was concentrated in vacuo to give a residue which was dissolvedin 100 ml. of benzene and the solution was concentrated to give solidcrude 1,2,3,4,5,6-hexahydroazepino[4,5- b]indole. This material wasdissolved in 10 ml. of ethyl acetate and treated with a solution ofcyclohexanesulfamic acid (0.5 g.) in 3 ml. of ethanol. The crystallinesalt which resulted was recrystallized from isopropylalcohol-Skellysolve B hexanes to give 0.17 g. (13.2 percent) ofl,2,3,4,5,6-hexahydroazepino[4,5-b]indole cyclohexanesulfamate ofmelting point l64-165 C.

Analysis:

Calcd. for C H N O s:

C, 59.15; H, 7.45; N, 11,50; S, 8.77.

Found:

C, 59.16; H, 7.47; N, 11.18; S, 8.62.

Preparation 16 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indole hydrochloride Asolution of 7.58 g. (0.0407 mole) of1,2,3,4,5,6-hexahydroazepinol4,5-b]indole, obtained as in Preparation inmethanol-ethyl acetate was acidified with methanolic hydrogen chloride.Crystallization of the resulting hydrochloride gave 6.74 g. (74.4percent) of l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride ofmelting point 250.5251.5 C. After recrystallization from methanol-ethylacetate, the material had a melting point of 247.5-248.5 C.

Analysis:

Calcd. for C, l-l, N Cl.

C, 64.71; H, 6.79; N, 12.58; Cl, 15.92.

Found:

C, 64.93; H, 7.08; N, 12.70; Cl, 16.10.

Preparation 17 9-Methoxy-l,2,3,4,5,6-hexahydroazepino-[ 4,5-b]indole andhydrochloride thereof A solution of3-benzyl-9-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.21 g.;0.017 mole) in a mixture of 47 ml. of acetic acid and 100 ml. of 95percent ethanol was treated with 10 percent palladium-on-carbon catalyst(l g.) and the mixture hydrogenolyzed at an initial pressure of 40p.s.i. in a Parr apparatus during 2 hours. The reaction mixture was thenfiltered through Celite (diatomaceous earth) and the filtrateconcentrated under reduced pressure to give a residue. The residue wasdissolved in water, cooled in an ice bath and made alkaline with sodiumhydroxide solution. The crystalline solid which was thus obtained wascollected by filtration, washed with water and dried in vacuo to yield3.53 g. of 9- methoxy- 1 ,2,3,4,5,6-hexahydroazepino-[4,5-b]indole ofmelting point 174-l 76 C.

A solution of this material in methanol was acidified with methanolichydrogen chloride and the resulting salt was crystallized from methanolto yield 3.96 g."(92.3 percent) of 9-methoxy- 1 ,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride of melting point 234-236C., which after recrystallization from methanol was 235235.5 C.

Analysis:

Calcd, for C,,,H, C1N O:

C,61.77; H, 6.78;C1, 14.03;N, 11.09.

Found:

C, 61.30; H. 6.85;Cl, 14.1 1; N, 10.99.

Preparation 18 S-Methoxy-l,2,3,4,5,6-hexahydroazepino-[4,5 -b]indole andhydrochloride thereof A mixture of 6.34 g. (0.0207 mole) of3-benzyl-8-methoxy- 1,2,3,4,5,6-hexahydroazepino[4,S-blindole, percentethanol (200 ml.) and 1 g. of 10 percent palladium-on-carbon catalystwas hydrogenolyzed at an initial pressure of 39.5 p.s.i. for 8 hours.The resulting mixture was filtered was filtered through Celite(diatomaceous earth) and the filtrate was concentrated in vacuo to givea residue. This residue was crystallized from methanol-ethyl acetate togive 3.24 g. (72.4 percent) of8-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole of melting point158160.5 C.

A solution of the base in methanol was acidified with methanolichydrogen chloride and the salt was recrystallized from water to give8-methoxy-l ,2,3,4,5,6-hexahydroazepino[ 4,5-b1indole hydrochloride ofmelting point 276-276.5 C. (dec.).

Analysis:

C, 61.77; H, 6.78; N, 11.09, Cl,14.03.

Found:

C, 62.03; H, 6.87; N, 11.17;Cl, 14.12.

Preparation 19 l0-Methoxy-1,2,3,4,5,6-hexahydroazepino-[ 4,5-b]indoleand hydrochloride thereof A mixture of3-benzyl-IO-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.66 g.;5.42 mmoles), 200 ml. of 95 percent ethanol and 0.5 g. of 10 percentpalladium-oncarbon catalyst was hydrogenolyzed at an initial pressure of41 p.s.i. over a period of 7 hours. The catalyst was removed byliltration through Celite (diatomaceous earth) and the filtrate wasconcentrated under reduced pressure to givel0-methoxyl,2,3,4,5,6-hexahydroazepino[4,5-b]indole as an oil.

This oil was dissolved in methanol and acidified with methanolichydrogen chloride. The resulting salt was crystallized frommethanol-ethyl acetate to give 1.04 g. (75.6 percent) of10-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]-indole hydrochloridewhich after additional recrystallization from methanol-ethyl acetate hada melting point of 236 C.

Analysis:

Calcd. for C H CIN O:

C, 61.77; H, 6.78; N, 11.09; Cl, 14.03.

Found:

C 61.95; H, 6.49; N, 10.98; C1, 14.06.

Preparation 20 7-Methoxy-1,2,3,4,5,6-hexahydroazepino-[ 4,5-b]indolehydrochloride A mixture of 1.61 g. (4.70 mmoles) of 3-benzyl-7-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride, ml. of 95percent ethanol and 200 mg. of 10 percent palladium-on-carbon catalystwas hydrogenolyzed for a period of 2.75 hours at an initial pressure of38 p.s.i. The resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure to give a residue which wascrystallized from methanol to give 0.782 g. of material ofmelting point275-27 7 C. and 0.233 g. of material of melting point 278-279 C. (85.4percent yield). This material was recrystallized from methanol to give7-methoxy-1,2,3,4,5,6-hexahydroazepino[ 4,5-b]indole hydrochloride ofmelting point 275-275.5 C.

Analysis:

Calcd. for C l-l ClN O:

C, 61.77; H, 6.78; N, 1 1.09; Cl, 14.03.

Found:

C,61.83; H, 6.71;N, 10.92; Cl, 13.85, 13.77.

Preparation 21 6-Methyll ,2,3,4,5,6-hexahydroazepino-[4,5- b]indole andhydrochloride thereof To an ice cold, stirred solution of1,2,3,4,5,6-hexahydroazepino[4,5-blindole (3.73 g.; 0.02 mole) in 200ml. of dry dimehtylformamide was added in a nitrogen atmosphere, 0.960g. of a 55 percent suspension of sodium hydride in mineral 011 (0.022mole of sodium hydride). This mixture was allowed to warm to 25 C. andstand for 2 hours. It was then cooled in an ice bath and treated during30 minutes with a solution of methyl iodide (1.37 ml.; 0.022 mole) in 25ml. of ether. The resulting solution was allowed to stand for 18 hoursat 25 C. It was then concentrated under reduced pressure to about 50 ml.and poured into water. The mixture was extracted four times with ether,the ether extracts combined, washed with brine, dried over anhydrouspotassium carbonate and concentrated under reduced pressure to give6-methyll,2,3,4,5,6-hexahydroazepino[4,5-b]indole as a residue. Thisresidue was redissolved in ethyl acetate and acidified with methanolichydrogen chloride and the resulting hydroscopic salt was crystallizedfrom methanol-ethyl acetate to give 3,19 g (75.3 percent) of materialwhich was again recrystallized from methanol-ethyl acetate to give6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b1indole hydrochloride ofamelting point of 214-2 1 C.

Analysis:

Calcd, for C, l-l ,N Cl:

C, 65.95; H, 7.24; N, 11.84; Cl, 14.98.

Found:

C, 66.35; H, 6.99; N, 11.78; Cl, 14.90. Preparation 226-Ethyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]- indole hydrochloride A coldsolution of 7.45 g. of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole in 400ml. of dry dimethylformamide in a nitrogen atmosphere was treated with1.92 g. ofa 55 percent suspension of sodium hydride in mineral oil. Themixture was stirred at room temperature for 3 hours, then cooled andtreated with a solution of 3.54 ml. of ethyl iodide in 50 ml. of ether.The addition took place over a period of minutes. The mixture was thenallowed to stir at room temperature for about 18 hours. The mixture wasthereupon concentrated under reduced pressure to give a residue whichwas dissolved in 250 ml. of water. The aqueous mixture was extractedthree times with ether and three times with methylene chloride. The twoextracts were worked separately, that is, washed with brine, then waterand finally dried over anhydrous potassium carbonate. Thereafter, thetwo extracts were combined and concentrated to give a residue which wassuspended on g. of silica gel and chromatographed over 450 g. of silicagel using 2 percent ethylamine-48 percent methanol-50 percent ethylacetate for elution. Fractions of about 150 ml. were collected. Thefirst band (A) consisted of fractions 6-9. The product was found infractions 14-21 (band B). The B fractions were combined and concentratedunder reduced pressure to give a residue which was dissolved in ethylacetate, cooled and acidified with methanolic hydrogen chloride. Theprecipitate which resulted was collected by filtration, washed withethyl acetate and dried in vacuo to yield 7.67 g. of material which wasrecrystallized from methanol and then three times from methanol-ethylacetate to give 6-ethyl-l,2,3,4,5,6- hcxahydroazepinol4,5-b]indolehydrochloride of melting point 253254 C. (dec.).

Analysis:

Calcd. for C H N CI:

C,67.05; H, 7.64; N, 11,17;Cl, 14.14. Found:

C, 67.10; H, 7.90; N, 1 1.47;Cl, 14.38.

Preparation 236-Methyl-9-methoxy-1,2,3,4,5,6-hexahydroazepinol4,5-b]indolehydrochloride and 3,6-dimethyl- 9-methoxyl,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride 1n the mannershown in Preparation 22, 9-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole was treated with sodiumhydride and then with methyl iodide to give a mixture of amines. Thismixture was separated by chromatography over silica gel using as eluanta mixture of 2 percent diethylamine-IS percent methanol-83 percent ethylacetate. Fractions 14-24 contained3,6-dimethyl-9-methoxyl,2,3,4,5,6-hexahydroazepino[4,5-b]indole whichwas converted to its hydrochloride with methanolic hydrogen chloride.Crystallization of this salt from methanol gave 3,6-dimethyl-9-methoxy-l ,2,3,4,5,6-hexahydroazepino[4,5-b]indolchydrochloride having a melting point of 270 C. (dec.). Analysis:

Calcd. for c,,H,,clN 0;

C, 64.16; H, 7.54; N, 9.98; CI, 12.63.

Found:

C, 64.20; H, 7.73; N, 9.82; Cl, 12.78.

Fractions 28-49 from the chromatographic column contained6-methyl-9-methoxy-l,2,3,4,5,6-hexahydr0azepino- [4,5-b]indole which wasconverted to its hydrochloride with methanolic hydrogen chloride.Crystallization of this salt from methanol gave 6-methyl-9-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride having a meltingpoint of 272 C. (dec.

Analysis:

Calcd. for C l-l ClN O:

C, 63.03; H, 7.18; N, 10.50; Cl, 13.29. Found:

C, 62.89; H, 7.25; N, 10.36; C1, 13.25.

Preparation 24 6-Methyll O-methoxyl,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride In the mannergiven in Preparation 23, lO-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole was treated with sodiumhydride and then with methyl iodide to give 6-methyl- 1 O-methoxy-l,2,3,4,S,6-hexahydroazepino[ 4,5-b]indole hydrochloride of melting point276.5278 C.

In the manner given in the above preparation other6-alkyll,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochlorides areprepared such as:

6-methyl-7-methoxyl ,2,3,4,5,6-hexahydroazepino[ 4,5,-b ]-indolehydrochloride 6-methyl-8-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]-indole hydrochloride 6-ethyl- 1 O-methoxyl,2,3,4,5,6-hexahydroazepino[4,5-b indole hydrochloride6-propyl-8-methoxy-l ,2,34,5,6-hexahydroazepino[4,5-b indolehydrochloride 6-isopropyl-7-methoxy-1,2,3,4,5,6-hexahydraozepino-[4,5-b]indole hydrochloride 6-methyl-9-fluoro-l,2,3,4,5,6-hexahydroazepino[4,5-b]-indole hydrochloride6-propyl-7-fluoro-l ,2,3,4,5,6-hexahydroazepino[4,5-b]-indolehydrochloride and the like.

The following examples illustrate the best mode contemplated by theinventor for carrying out the invention but are not to be construed aslimiting the scope thereof.

EXAMPLE 1 One thousand tablets for oral use, each containing mg. of6-methyl-l ,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride areprepared from the following ingredients:

b]indolc hydrochloride, hydrate 100 Gm. Dicalcium phosphate 200 Gm.Mcthylccllulosc, U.S.P. 15 cps.) 6.5 Gm. Talc 30 Gm. Calcium stearate3.5 Gm.

EXAMPLE 2 One thousand two-piece hard gelatin capsules for oral use,each capsule containing 10 mg. of6-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride hydrateand 15 mg. of phenobarbital are prepared from the following ingredients:

6-methyl-l,2,3,4,5,6-hexahydroazepino [4,5-

b]indolc hydrochloride, hydrate l0 Gm Phenobarbital l5 Gm. Corn starchGm Talc 60 Gm Magnesium stearate 25 Gm.

The finely powdered materials are mixed thoroughly, then filled intohard gelatin capsules of appropriate size.

The foregoing capsules are useful in treatment of obesity at a dosage of1 capsule twice a day.

EXAMPLE 3 An aqueous oral preparation containing in each 5 ml., 50 mg.of 6-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]-indole hydrochloride,hydrate is prepared from the following ingredients:

6 methyl-l ,2,3,4,5,6,-hexahydroazepino- [4,5-blindole hydrochloride,hydrate I Gm. Methylparaben 7.5 Gm. Propylparaben 2.5 Gm. Saccharinsodium l2.5 Gm. Glycerin 3000 ml. Tragacanth powder 100 G111. Orange oilflavor l0 Gm. F. D. and C. Orange dye 7.5 Gm. Deionized water q.s.10,000 ml.

The foregoing composition is useful in the control of obesity inchildren at a dosage of l teaspoonful every 6 hours.

EXAMPLE 4 A sterile aqueous suspension for intramuscular injection,containing in each ml. 100 mg. of6-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride,hydrate, is prepared from the following ingredients:

(i-methyl-l,2,3,4,5,6-hexahydroazepino-[4,5-

b]hydrochloride, hydrate 100 Gm. Sodium carhoxymcthylccllulose, lowviscosity l0 Gm. Polysorbate 80, U.S.P. 4 Gm. Propylparuhcn, USP. 0.4Gm. Water for injection q.s. 1,000 ml.

I The foregoing parenteral suspension is useful in the treatment of anobese adult at a dosage of 1 ml. twice a day.

EXAMPLE 5 One thousand tablets are prepared from the following types andamounts of ingredient:

o-methyll ,2,3,4,5,6-hexahydroazepino-[4,5-

blindole hydrochloride, hydrate 500 Gm. Citric acid, powder 50 Gm. Talc50 Gm. Magnesium stearate 2.5 Gm. v

The ingredients are mixed together and slugged. The slugs are screenedand pressed into tablets. The foregoing tablets are useful in thetreatment of obesity at a dose of 1 every 6 hours.

EXAMPLE 6 One thousand hard gelatin capsules are prepared from thefollowing types and amounts ofingredients:

6-methyll ,2,3,4,5,6-hexahydroazepino-[4,5-

b]indo|e hydrochloride, hydrate 25 Gm Diethylpropion hydrochloride l5 GmStarch 25 Gm. Terra alba 75 Gm. Magnesium stearate 3 5 Gm The ringredients are powdered and mixed together until uniformly dispersedand filled into hard gelatin capsules.

The capsules are useful in the treatment of obesity at a dose of 1capsule every 6 hours.

EXAMPLE 7 One thousand tablets for oral administration, each containing25 mg. of 6-methyl-l,2,3,4,5,6-hexahydroazepino-[4,5-

b]indole hydrochloride, hydrate and 16.2 mg. of chlor-' promazine areprepared from the following types and amounts of ingredients:

o-methyl-l ,2,3,4,5,6-hexahydroazepino-[4,5-

b]indole hydrochloride, hydrate 25 Gm. Chlorpromazine 16.2 Gm. LactoseI75 Gm. Starch l5 Gm. Magnesium stearate 1.5 Gm.

The ingredients are thoroughly mixed and slugged. The slugs are brokendown by forcing through a screen and the resulting granules are thencompressed into tablets.

The preceding tablets are useful for the treatment of obesity in adultsat a dose of 1 tablet twice a day.

EXAMPLE 8 One thousand ml. of a syrup is prepared from the followingtypes and amounts of ingredients:

6-methyll ,2,3,4,5,6-hexahydroazepino [4,5-

b]indole hydrochloride, hydrate Cocoa syrup U.S.P., q.s.

50 Gm. 1000 ml.

The 6-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]-indole hydrochloridehydrate is stirred with cocoa syrup until dissolved.

The syrup is useful in the treatment of adult obesity at a dose of lteaspoonful four times a day.

EXAMPLE 9 One thousand ml. of an elixir, containing 100 mg. of 6-methyl- 1 ,2,3,4,5,6-hexahydroazepino[4,5-b1indole hydrachloride hydrateand 8.1 mg. of phenobarbital in each 5 ml., is prepared from thefollowing types and amounts of ingredients:

fi-methyll ,2,3,4,5,6 tetrahydroazepino-[ 4,5-

blindolc hydrochloride, hydrate 20 Gm. Phenobarbital 1.62 Gm. Citricacid 0.1 Gm. F.D.C. Red No. l 0.04 Gm. Saccharin 0.l Gm. Sucrose 200 Gm.Oil of Spearmint 0.] Gm. Oil of Wintergreen 0.1 Gm. Polysorbate U.S.P. lGm. Ethanol 200 ml. Glycerin ml. Water q.s. I000 ml.

EXAMPLE 10 A sterile aqueous solution for parenteral administration,containing 50 mg. of 6-methyl-l ,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride hydrate in each ml., is prepared from thefollowing types and amounts of ingredients:

6-methyll .2,3,4,5 ,6-tetrahydroazepino-[ 4,5-

b]indole hydrochloride hydrate 50' Gm. Chlorpromazine hydrochloride 5Gm. Water for injection q.s. 1,000 mlv The6-methyl-l,2,3,4,5,fi-hexahydroazepino[4,5-b1indole hydrochloridehydrate and chloropromazine hydrochloride are dissolved in the water forinjection and the solution sterilized by filtration. The sterilesolution is filled into 2 ml. sterile vials and sealed.

The composition is useful in the treatment of anxiety and obesity at adose of l ml.

EXAMPLE l 1 One thousand capsules for oral administration are preparedfrom the following ingredients:

o-methyl-l ,2,3,4,5,6-hexahydroazepino-[4,5-

b]indole hydrochloride, hydrate micropulverized 100 Gm. Lactose, hydrous132.5 Gm. Magnesium stearate powder 2.5 Gm.

EXAMPLE 12 One thousand capsules for oral administration are preparedfrom the following ingredients:

b]indole hydrochloride hydrate micropulverized 50 Gm. Lactose. hydrous207.5 Gm. Magnesium stearate powder 2.5 Gm.

The powders are mixed thoroughly and filled into No. 3 hard gelatincapsules.

The capsules are useful in the treatment of obese children at a dose ofone capsule three times a day.

EXAMPLE 13 One thousand suppositories, each weighing 2.5 Gm. andcontaining 250 mg. of6-methyl-l,2,3,4,5,6-hexahydroazepino-[4,5-b]indole hydrochloride,hydrate are prepared from the following types and amounts ofingredients:

6-methyl-l 2.3,4,5,-hexahydroazepino-l 4,5-

b]indole hydrochloride, hydrate 250 Gm. Propylene glycol 165 Gm.Polyethylene glycol 4,000 q.s. 2,500 Gm.

EXAMPLE 14 Following the procedure of the preceding Examples 1 to 13,inclusive, dosage forms are similarly prepared by substituting anequivalent amount of 6-ethyl-1,2,3,4,5,6-hcxahydroazepino[4.5-b]indolehydrochloride 6-methyl-lO-methoxy-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride 6-methyl-9-methoxyl,2,3,4,5,6-hexahydroazepino-[4,5-b ]indole hydrochloride, for the6-methyl-l ,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride of theExamples.

I claim:

1. A therapeutic composition for inducing anorexia comprising, in unitdosage form, from about 5.0 mg. to about 500 mg. of a member selectedfrom the group consisting of compounds of the formula:

wherein R and R are selected from the group consisting of hydrogen,alkoxy and alkyl containing from one to three carbon atoms, inclusive,and halogen; and R is alkyl containing from one to three carbon atomsand the pharmacologically acceptable acid addition salts thereof inassociation with a pharmaceutical carrier.

2. The composition of claim 1 wherein the compound selected is6-methyl-1,2,3,4,5,-hexahydroazepino[4,5-b1indole hydrochloride. I

3. A process for inducing anorexia comprising the administration of anappetite suppressing amount of a member selected from the groupconsisting of compounds of the formula wherein R and R are selected fromthe group consisting of hydrogen, alkoxy and alkyl containing from oneto three carbon atoms, inclusive, and halogen; and R, is alkylcontaining from one to three carbon atoms and the pharmacologicallyacceptable acid addition salts thereof to an obese human subect.

4. The process of claim 3 wherein from about 20 mg. to about 1,000 mg.of said member is administered per kilogram body weight ofsaid subject.

5. The process of claim 3 wherein from about 5 mg. to about 500 mg. ofsaid member is administered.

6. The process of claim 3 wherein the compound selected is 6-methyl-l,2,3,4,5,6-hexahydroazepino[ 4,5-blindole hydrochloride.

7. The process of claim 4 wherein the compound selected is 6-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride.

8. The process of claim 5 wherein the compound selected is 6-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride.

2. The composition of claim 1 wherein the compound selected is6-methyl-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole hydrochloride.
 3. Aprocess for inducing anorexia comprising the administration of anappetite suppressing amount of a member selected from the groupconsisting of compounds of the formula
 4. The process of claim 3 whereinfrom about 20 mg. to about 1, 000 mg. of said member is administered perkilogram body weight of said subject.
 5. The process of claim 3 whereinfrom about 5 mg. to about 500 mg. of said member is administered.
 6. Theprocess of claim 3 wherein the compound selected is6-methyl-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole hydrochloride.
 7. Theprocess of claim 4 wherein the compound selected is6-methyl-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole hydrochloride.
 8. Theprocess of claim 5 wherein the compound selected is6-methyl-1,2,3,4,5,6-hexahydroazepino(4,5-b)indole hydrochloride.